P1082: RESULTS FROM A PHASE 1/2 STUDY OF TANDEM, BISPECIFIC ANTI-CD20/ANTI-CD19 (LV20.19) CAR T-CELLS FOR MANTLE CELL LYMPHOMA
Authors: Nirav N Shah, Timothy Fenske, Bryon Johnson, Aniko Szabo, Sumana Devata, Walter Longo, Tyce Kearl, Anthony Zamora, Parameswaran Hari, Dina Schneider, Mehdi Hamadani
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by presence of t(11;14) and bright CD20 expression. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL is effective but limited by relapse and high rates of Grade 3+ cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), with 15% and 31% of patients (pts) experiencing such toxicities, respectively. We hypothesized that lentiviral bispecific CAR-T cells targeting both CD20 and CD19 B-cell antigens (LV20.19 CAR) with 4-1BB co-stimulatory signaling domain will improve clinical outcomes in R/R MCL while minimizing toxicity. Aims: To determine the efficacy of LV20.19 CAR T-cell therapy in R/R MCL. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R MCL. LV20.19 CAR T-cells were manufactured onsite using the CliniMACS Prodigy device with IL7/IL15 for cell expansion. After safety run-in, we opened a 14-patient single stage Phase II MCL arm with flexible 8/12-day manufacturing (MF) and goal of fresh infusion with a target complete response (CR) rate of 50% to exceed the historical CR rate of Ibrutinib in R/R MCL of 20%. Results: To date, 14 MCL pts have received LV20.19 CAR T-cells at the target dose of 2.5x10e6 cells/kg (Phase 1=3 pts and Phase 2=11 pts). Eleven of 14 pts received 8-day manufactured CAR-T cells while 3 pts received a 12-day product. MF was successful in 100% of pts and all but 2 pts received a fresh (non-cryopreserved) infusion. Cryopreservation was required in both pts due to clinical need: infection (n=1) and rapid tumor growth necessitating bridging after apheresis (n=1). Median age was 63 years and median prior lines of therapy was 5. Eleven of 14 pts (79%) progressed on a Bruton’s Tyrosine Kinase inhibitor (BTKi) and 5 (36%) of these pts also progressed on a non-covalent BTKi (pirtobrutinib) administered on a clinical trial. LV20.19 CAR T-cells produced in the CliniMACS Prodigy had robust expansion with mean 5.2x10e8 CAR T-cells obtained on Day 7 of MF. The Day 28 ORR was 100% (CR=64% and PR=36%). At day 90, among 12 evaluable pts, the ORR remained 100% (CR=92% and PR=8%) and the number of CR pts in the Phase 2 cohort exceeded prespecified threshold meeting the primary endpoint of this study. Nine of 12 assessed pts were minimal residual disease (MRD) negative by ClonoSEQ assay between Days 28-65 post CAR. With median follow-up of 22 months among surviving pts, only 1 patient has relapsed with MCL. In terms of toxicity, 13 pts (93%) experienced CRS, all Grade 1-2 (no Grade 3+ events). Three pts (21%) had ICANS, 1=Grade 2 and 2=Grade 3. One Grade 3 ICANS patient was found to have incidental MCL involvement of CSF during evaluation of neurotoxicity. No patient required ICU level care in the first 28-days. There was one non-relapse mortality (NRM) event due to gram negative sepsis at Day +46 post CAR. The 1-year cumulative incidence of relapse and NRM were 0% and 7%, respectively, while the 1-year PFS and OS were 93%. Median duration of PFS, OS, and duration of response were not met (Figure 1). Summary/Conclusion: Bispecific LV20.19 CAR T-cells expanded with IL7/IL15 and manufactured onsite are safe and efficacious for R/R MCL with a day 90 ORR of 100%, and only one relapse to date with a median follow-up of nearly 2-years. Toxicity profile was encouraging with no Grade 3+ CRS and low rates of Grade 3+ ICANS. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with R/R MCL.Keywords: CAR-T, Lymphoma therapy, Mantle cell lymphoma, Hematological malignancy